Projects / Programmes
Etiology, inflammatory proteins and genetic polymorphism in patients with solitary and multiple erythema migrans
| Code |
Science |
Field |
Subfield |
| 3.01.00 |
Medical sciences |
Microbiology and immunology |
|
| Code |
Science |
Field |
| B510 |
Biomedical sciences |
Infections |
| Code |
Science |
Field |
| 3.01 |
Medical and Health Sciences |
Basic medicine |
Lyme borreliosis, erythema migrans, post Lyme borreliosis symptoms, inflammatory proteins, genetic polymorphism, IL-23, TH17 immune reponse
Researchers (19)
Organisations (2)
Abstract
Lyme borreliosis (LB), caused by Lyme borreliae (B. burgdorferi s.l.), is the most common tick-borne disease in the Northern Hemisphere. The infection in Europe is due predominantly to B. afzelii and B. garinii, and rarely to B. burgdorferi, which is the only causative agent in North America. The most common clinical manifestation is a solitary skin lesion called erythema migrans (EM), however, in a subset of patients borreliae may disseminate in blood to other skin sites and organ systems.
The underlying mechanisms that lead to disseminated disease remain poorly understood and could involve both host and microbial factors. For example, subtyping of B. burgdorferi strains in the US has led to the identification of certain genotypes that have greater propensity to disseminate, are more inflammatory, and cause more symptomatic infection. In addition, genetic risk factors in the host, such as polymorphism in the TLR1 gene, are beginning to be idenified. However, the possibility that sub-strains of Borrelia species in Europe, in combination with host susceptibility genes, vary in their ability to disseminate and cause more severe disease has not been tested.
Although most patients with EM recover completely after antibiotic therapy, approximately 10% report persistent or newly developed subjective symptoms such as headache, fatigue, myalgia, and arthralgia in the months after antibiotics. These post-Lyme symptoms have become a substantial clinical challenge. The underlying mechanisms are not known and may be multifactorial, and there are no standardized treatment strategies. Our recent results indicate that post-Lyme symptoms could be due to immune system abnormalities. We found that a subset of patients with subjective symptoms after antibiotic therapy for EM and a culture negative result for borreliae, have high levels of IL-23, a TH17-associated cytokine, which correlate with elevated autoantibody responses. These findings demonstrate that rather than persistent infection, post-Lyme symptoms could be due to dysregulated TH17 immune respones.
Thus, we hypothesize that the differences in dissemination and pathogenesis, including the possibility for post-Lyme symptoms, result from altered inflammatory immune responses that are shaped by both host and microbial factors. To identify the causative microbial agents and host immune factors in the pathogenesis of LB we will use a new, cutting edge approach including microbiological, immunological, and genetic analyses of clinical specimens from patients with clearly-defined LB manifestations.
We propose the following specific aims:
Aim 1) To identify the genotypes within the European B. burgdorferi s.l. species that vary in virulence, including the ability to disseminate and persist, by optimizing a genotyping system and correlating individual subtypes with clinical findings from the same patients. Borrelia genotypes will be determined in patient skin and blood samples by restriction fragment length polymorphism and multilocus sequence typing. Persistence will be assessed by tissue culture, PCR, and serological analyses in skin and blood from patients before and after treatment.
Aim 2) To determine the immune mechanisms in LB pathogenesis by characterizing patients' immune protein profiles, including TH17 responses, and disease-relevant genetic variants and correlate these results with clinical findings in the same patients. Cytokines and chemokines representative of innate and adaptive immune responses will be assessed in sera and skin biopsies of patients during active infection and after treatment using Luminex or PCR. Genetic variants will be assessed by ImmunoChip.
Aim 3) To develop clinically-relevant predictive models using mathematical modeling and biostatistics to correlate strain differences and immune profiles with clinical parameters, frequency of dissemination, severity of disease, and presence of post-Lyme symptoms.
Significance for science
Results of our research work contribute to the understanding of the pathogenesis of Lyme borreliosis and have important consequences for clinical practice. Our results confirmed that the more convenient, safer and cheaper therapeutic approach to treating multiple erythema migrans with oral antibiotics is non-inferior to intravenous therapy.
Significance for the country
By publicing of our results in international scientific literature we contribute to the international recognition of Slovenia on the field of infectology. Our results showed that the cheaper and patient more friendly oral treatment is non-inferior to intravenous therapy of multiple erythema migrans.
Most important scientific results
Annual report
2014,
2015,
final report
Most important socioeconomically and culturally relevant results
Annual report
2015,
final report
